Poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) are unique biocompatible polymers used in a variety of biomedical implant devices, such as controlled and targeted drug delivery systems, adhesion barriers, and tissue engineering applications. In an interesting commentary on a published paper by Sheth and Leckband (Sheth, S. R. and Leckband, D. Measurements of attractive forces between proteins and end-grafted poly(ethylene glycol) chains, Proc. Natl. Acad. Sci., 94, 8399-8404 (1997)) by Israelachvili (Israelachvili, J., The different faces of poly(ethylene glycol), Proc. Natl. Acad. Sc., 94, 8378-8379 (1997)), he discusses the characteristics of PEO, especially with regards to miscibility in aqueous media, ability to repel proteins and being repelled by proteins while enabling the dissolution and controlled release of drugs.
U.S. Pat. No. 6,677,362 discloses the use of solid dispersions of water-insoluble drugs in hydrophilic polymers, such as polyvinylpyrrolidone (PVP), or high molecular weight PEO, from aqueous solutions for improved bioavailability. U.S. Pat. No. 4,188,373 discloses the use of PEO-PPO-PEO block copolymers as sol-gel vehicles in pharmaceutical compositions that are soluble in water at room temperature, and has a gel transition temperature in the body temperature range (25-40° C.). The primary constraint of drug incorporation by this method arises from the severe differences in the water solubility of the polymer and the drug resulting in poor drug-loading capacity and efficiency.
U.S. Pat. No. 4,911,926 discusses the use of aqueous and non-aqueous compositions comprising polyoxyalkylene block copolymers in reducing post surgical adhesion formation. However. PEO and PPO are not biodegradable, and hence their use is restricted to low molecular weights so that they can be resorbed easily by the body. This seriously limits the use of PEO and PEO-PPO-PEO block copolymers by themselves as an adhesion barrier because low molecular weight PEO and PEO-PPO-PEO are absorbed at a much faster rate than the wound healing process. Also, low molecular weight PEO and PEO-PPO-PEO are soft materials and their applications are limited to biomedical areas where strength is not a requirement.
Aliphatic polyesters as medical implant devices have been studied extensively. Kulkarni, et al., discuss the development of synthetic bioresorbable polyesters produced by ring opening polymerization of L-lactide for implant studies (Kulkarni, et al., Biodegradable poly(lactic acid) polymers, J. Biomed. Mater. Res., Vol 5, 169-181, (1971)). These aliphatic polyesters are characterized by high strength (that can be processed into biomedical articles), low elongation, biocompatibility and degradation over a long period of time.
In an attempt to improve the biodegradability while not impacting on the tensile properties. U.S. Pat. No. 3,636,956 discloses the development of high strength aliphatic polyesters, viz. copolymers of L-lactide and glycolide that are fast degrading. Similarly, U.S. Pat. No. 4,438,253 discloses multiblock copolymers produced by transesterification of PEO and poly(glycolic acid) for use in surgical articles with good flexibility and faster biodegradability.
U.S. Pat. No. 4,826,945 discloses the synthesis of ABA type block copolymer composed of polyethylene oxide (PEO) and α-hydroxy carboxylic acid using a one-step process. The process essentially involves the ring opening polymerization of L-lactide, glycolide, caprolactone or other similar monomers using PEO of desired molecular weight and in the presence of catalyst at high temperatures. The ABA block copolymer generated is low molecular weight with terminal hydroxyl groups that is chain extended to very high molecular weights by reacting with a diisocyanate to yield polyetheresterurethane. Unlike polyesters that are rigid and having low extensibility, these polyetheresterurethanes are elastomeric, i.e. flexible and having high extension.
U.S. Pat. No. 4,826,945 discloses the use of Sb2O3 as the esterification catalyst for the ring opening polymerization, while the use of tin octoate as an efficient ring opening polymerization (esterification) catalyst has been reported in U.S. Pat. No. 3,839,297. U.S. Pat. No. 5,711,958 describes the sequential use of stannous octoate as a catalyst for the esterification reaction and chain extension reaction with a diisocyanate. The advantage of using stannous octoate as the esterification catalyst lies in its extended use as a catalyst in the subsequent polyurethane reaction.
U.S. Pat. Nos. 5,711,958; 6,136,333; 6,211,249, 6,696,499; 7,202,281 further discuss the use of AB and ABA type polymers as adhesion barriers films in their hydrated form. However, significant amounts of PEO are required in the polymer to enable it to successfully function as an adhesion barrier. Even so, the efficacy of the entire polymeric material (in the form of films) to inhibit post surgical adhesions is limited and as much as one-third of the test population treated with these polymers reportedly developed severe adhesions
The use of A-B, ABA and BAB type block copolymers, wherein, A=PEO or PEO-PPO and B=polyesters or poly(ortho esters) as bioresorbable drug delivery systems has been reportedly discussed in patent disclosures and journal literature. U.S. Pat. No. 4,526,938 discloses the use of ABA type of polyesters for use in tunable sustained release of drugs. By manipulating the amount of hydrophobic polyester component in the copolymer, it was possible to adjust the length of time for sustained drug release. U.S. Pat. No. 7,649,023 discloses the use of low molecular weight PEO in the development of oligomeric multiblock polyesters as free flowing liquid or water-reconstitutable drug carriers.
Whereas the above literature teaches the use of block copolymers containing poly(oxyalkylene) units for making different biomedical devices, there are other arrangements of the hydrophilic PEO units within the polymer structure that are recently being utilized for different applications. WO 2009/073192 A2 discloses the use of pendant side chain crystallizable (SCC) polymers as carriers for drug release applications. Polymeric release compositions with systems and methods for delivering release materials, for e.g. drugs and other bioactive materials have been described. In addition, use of the compositions as tissue scaffolds, ocular inserts, for delivery of nucleotides, and in drug eluting stent applications have been described.
A recent review article, (Neil Ayres (Ayres, N., Polymer brushes: Applications in biomaterials and nanotechnology, Polymer Chemistry, Vol 1, 2010, 769-777)) examines the uses of surface confined macromolecules or polymer brushes for surface and interface applications in areas of biomaterials and nanotechnology. As described earlier, pegylated surfaces (and other similar hydrophilic poly(oxyalkylene) amphiphiles) are “first approach” strategy for developing biocompatible devices. Leckband et al. (Leckband et al., Grafted (polyethylene oxide) brushes as non-fouling surface coatings, J. Biomater. Sci. Polymer Edn., 10(10), 1999, 1125-1147) describe the theoretical and quantitative aspects of grafted PEO brushes in preventing protein adsorption. They determined that controlling the graft density and molecular weight of PEO can be utilized to control, prevent or retard protein adsorption. Furthermore, the polymer segments of the grafted PEO brushes under hydrated conditions are predominantly amorphous.
Recently numerous accounts of using pendant side chain containing amphiphilic polyurethanes for improved control and stabilization of colloidal dispersions in aqueous media have been reported for non-medical applications. WO 2009013316 describes the use of pendant polyoxyalkylene based 1,3 diols (Tegomer D3403, Tegomer D 3123 and Tegomer D3409) in the preparation of a water-dispersible polyurethane using a polyisocyanate crosslinker. WO 2007023145 discloses the use of pendant MPEG based 1,3 diol for the synthesis of polyurethane dispersant coatings with good pigment dispersibility and stability.
The use of PVP as an adhesive for general purposes is known. Good adhesion to plastic surfaces, such as polyethylene terephthalate (PET) is disclosed in commercially available product literature, such as by BASF. U.S. Pat. No. 5,143,071 discloses the development of highly conducting non-stringy PVP and PEO based adhesive gels for application to skin to provide electrical contact for medical devices.
U.S. Pat. No. 7,727,547 describes a tissue adhesive formulation which consist of polymerizable and/or cross-linkable material in particulate form, the said material being in admixture with particulate material comprising tissue-reacting functional groups. The patent also describes application of such formulation to one side of a core of a naturally occurring or synthetic polymeric material. The adhesive polymer described in the patent comprises of reaction product of poly(N-vinyl-2-pyrrolidone-co-acrylic acid) copolymer and a reactant comprising a tissue-reacting functional group.
U.S. Pat. No. 5,508,036 claims a device for preventing adhesions which comprises a composite of a first layer and a second layer, each of which comprises a biodegradable polymer of different pore size and optionally with an adherence layer to support the adhesion barrier and to enable attachment of the device without suturing.
The object of the invention is the development of compositions comprising biodegradable amphiphilic polyesters have the advantage of retaining better mechanical integrity prior to onset of degradation in contrast to the ABA triblock biodegradable polymers according to the prior art described above.
This is achieved by a composition comprising at least one polymer having the structure A-B-A′, wherein A and A′ may be the same or different and each is a degradable polyester component and wherein B is the reaction product resulting from the reaction between a diol, having one or more pendant oligomeric or polymeric groups, and A and A′.
A further advantage of the compositions according to the invention is that the surface of a device manufactured from the compositions is hydrophilic or hydrophobic enriched and presents superior functional properties compared to the ABA triblock copolymers of the prior art. For example the polymers according to this invention can form a barrier for preventing post surgical adhesions.
Another advantage of the compositions according to the invention is that the amphiphilic property of the polymeric material in the compositions of the invention enables the dispersion and uniform distribution of bioactive agents in the polymer matrix. In this way the bioactive agents can released into the immediate tissue environment or intended site at a desired dose rate as the polymer degrades over the period of time.
Another advantage of the compositions according to the invention is that the ratio of the alkylene oxide units to the degradable ester linkages in the polymer composition allows tunability of the mechanical properties desired for a specific application.
Another advantage of the compositions of the present invention is that the compositions can be formed into a film which can be used in a bioresorbable adhesive patch containing a PVP based adhesive coated on the film of the composition according to the invention.